The goal of this laboratory is to understand how T cells respond to self-antigens in the context of tumor immunity and autoimmune disease. As they mature in the thymus, most high avidity self-reactive T cells are deleted, although a small fraction escape negative selection and emigrate to the periphery. These residual cells remain tolerant of self-antigen in the absence of abnormal stimuli. However, under certain circumstances, they may become activated to cause pathologic responses. By understanding how T cells become activated and what regulates their tolerant state, we plan to utilize this knowledge to elicit potent anti-tumor responses and to define novel approaches to treating autoimmune disease.There are 3 on-going projects in this laboratory. The first project is a melanoma-related project that is examining tolerance to a pigmentation antigen, TRP-2, which is co-expressed by both melanoma cells as well as their non-transformed counterparts, melanocytes. In this model system, we have observed that sensitization to TRP-2 can elicit autoimmunity (which manifests as depigmentation of the hair) in the absence of tumor immunity. This past year, we have observed that provision of the cytokine GM-CSF can convert the autoimmune response into an anti-tumor immune response. This apparent induction of tumor immunity is due to an increase in tumor antigen-specific T cells as well as a concomitant increase in dendritic cells. On-going studies are determining the phenotype and functionality of these recruited dendritic cells.The second project involves studying T cell reactivity to tumor antigens using a murine model of prostate cancer. In the 'TRAMP' model, mice develop primary prostatic tumors as a result of transgenic expression of the SV40 T antigen (TAg) under the control of a prostate-specific promoter. In our studies, TRAMP mice are adoptively transferred with T cells derived from TcR transgenic mice that have specificity for either a class I- or class II-restricted epitope of TAg. In our preliminary studies, we have observed that transfer of the class I-restricted T cells into TRAMP mice results in an initial proliferative expansion followed by deletion from the peripheral lymphoid organs, but retention in the prostate, the site of tumor formation. This past year, we have observed that the T cells that remain in the prostatic tissues are unresponsive to antigenic stimulation unless IL-2 is provided. However, vaccination of mice with a dendritic cell vaccine causes an increase in the accumulation of T cells in the prostate. Similarly, co-transfer of T antigen-specific CD4+ T cells also prevents T cells from deletion. Most strikingly, we have observed that both dendritic cell vaccine and transfer of CD4+ cells can rescue prostate tumor-infiltrating T cells from anergy induction. These findings have critical importance for immunotherapy of cancer. On-going studies are determining gene expression profiles of T cells following anergy induction as well as characterization of signals that recruit T cells to the prostate.When eliciting an anti-tumor immune response, it is believed that the T cell response to tumor-associated antigens may resemble an autoimmune response. In support of this idea, productive immune responses against melanoma often result in vitiligo, an autoimmune destruction of melanin-producing cells. In the third project, we are therefore studying disruption of T cell tolerance to neural antigens relevant to the human autoimmune disease, multiple sclerosis (MS). We use a murine model of CNS inflammation, experimental autoimmune encephalomyelitis (EAE). We previously reported that blockade of CTLA-4, an inhibitory receptor expressed by T cells, not only exacerbates EAE in susceptible mice, but it can also induce disease in resistant mice (e.g., BALB/c mice). Our on-going studies are characterizing the mechanism by which CTLA-4 blockade reverses resistance to EAE. In addition, we have recently undertaken studies to examine the role of regulatory T cells in EAE-resistant mice.